POS1028 SUCCESSFUL TREATMENT OF MURINE RHEUMATOID ARTHRITIS MODELS WITH CENERIMOD, A SELECTIVE S1P1 RECEPTOR MODULATOR, HIGHLIGHTS THE BENEFIT OF S1P IMMUNOMODULATION IN RHEUMATIC DISEASES
Authors: T. Hoyler, M. Bulle, J. Scherer, C. Wyss, S. Froidevaux, M. Martinic
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Since the discovery of the sphingosine-1-phosphate (S1P) pathway and its potentially beneficial role of inducing lymphocyte retention and subsequent immunomodulation [1], several small molecule S1P receptor modulators have been approved for the treatment of diverse autoimmune diseases such as multiple sclerosis and ulcerative colitis. Cenerimod, a selective S1P<sub>1</sub> receptor modulator, has shown efficacy in preclinical models of systemic lupus erythematosus (SLE), systemic sclerosis and Sjögren's syndrome [2-4] and is now entering a Phase III clinical trial (OPUS; NCT05648500) in patients with moderate to severe SLE. <h3>Objectives</h3> We investigated the efficacy of cenerimod in modulating disease progression in preclinical models of rheumatoid arthritis (RA). <h3>Methods</h3> We analyzed the efficacy of cenerimod in several models of RA in mice and rats. Disease-relevant biomarkers such as autoantibody development and chemokine secretion were measured to gain a deeper understanding of the mode of action of S1P<sub>1</sub> receptor modulation in these RA models. <h3>Results</h3> In mouse RA models, prophylactic treatment with cenerimod inhibited the acute inflammatory response post antigen challenge and prevented autoantibody formation, thus completely preventing the initiation of disease. Cenerimod treatment at disease onset further showed a strong reduction of joint inflammation and significantly delayed clinical symptoms and the secretion of several pro-inflammatory chemokines. Although corticosteroid treatment is frequently administered as an adjunct treatment for interventional disease management in RA, its systemic toxic effects do not permit long-term usage to control disease activity in patients with rheumatic diseases [5]. In rats, cenerimod treatment prevented disease development dose-dependently when given directly at initiation of disease, while treatment at disease onset stopped further inflammation of the joints. Further, treatment with low-dose cenerimod limited joint inflammation to the same extent as low-dose corticosteroid treatment while not having a similar negative impact on body weight over the duration of the experiment. <h3>Conclusion</h3> S1P receptor immunomodulation is a highly effective treatment option for murine models of RA with translational value for rheumatological indications. Combined with the published data on rheumatic diseases, we believe that S1P<sub>1</sub> receptor modulation by cenerimod will benefit patients suffering from RA who are underserved by the current treatment landscape. <h3>References</h3> [1] Cyster J &amp; Schwab S: Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol 2012; 30 [2] Strasser DS, et al.; Preclinical to clinical translation of cenerimod, a novel S1P1 receptor modulator, in systemic lupus erythematosus. RMD Open 2020; 6(2) [3] Kano M, et al.; Attenuation of murine sclerodermatous models by the selective S1P1 receptor modulator cenerimod. Sci Rep. 2019; 9(1) [4] Gerossier E, et al.; Cenerimod, a selective S1P1 receptor modulator, improves organ-specific disease outcomes in animal models of Sjögren's syndrome. Arthritis Res Ther 2021; 23(1) [5] Hua C, et al.; Glucocorticoids in rheumatoid arthritis: current status and future studies. RMD Open 2020; 6 (1) <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Thomas Hoyler Shareholder of: Idorsia Pharmaceuticals Ltd., Employee of: Idorsia Pharmaceuticals Ltd., Maxime Bulle Shareholder of: Idorsia Pharmaceuticals Ltd., Employee of: Idorsia Pharmaceuticals Ltd., Jérémy Scherer Shareholder of: Idorsia Pharmaceuticals Ltd., Employee of: Idorsia Pharmaceuticals Ltd., Conrad Wyss Employee of: Idorsia Pharmaceuticals Ltd., Sylvie Froidevaux Shareholder of: Idorsia Pharmaceuticals Ltd., Employee of: Idorsia Pharmaceuticals Ltd., Marianne Martinic Shareholder of: Idorsia Pharmaceuticals Ltd., Employee of: Idorsia Pharmaceuticals Ltd.